In recent years, there has been a marked increase in the prevalence of obesity and insulin-resistant syndromes such as Type II Diabetes Mellitus and the metabolic syndrome. This increasing public health epidemic has dramatically emphasized the need to understand in more detail how insulin regulates metabolism and how this process gets perturbed during hyperinsulinemia. Work from the Principal Investigator as well as other scientists have contributed to unraveling a signaling pathway by which insulin regulates metabolism in liver, muscle and adipose tissue. Central to this signaling cascade is the serine/threonine protein kinase Akt, also known as Protein Kinase B. Previous work from the Principal Investigator's laboratory has demonstrated that each of the three Akt family members each has distinct roles in normal physiology. Thus, one of the major goals of this grant proposal understands the mechanism by which this isoform specificity is conferred. In particular, these studies focus on insulin action in the liver, where Akt appears to be an obligate intermediate in mediating many of insulin's metabolic outputs. The isoform specificity in hepatic metabolism is evident in liver, in that Akt2 deletion abrogates control of lipogenic gene expression, but insulin is still capable of regulating the genes encoding gluconeogenic proteins. Nonetheless, Akt2-deficient livers display insulin resistance in terms of glucose output in spite of the preserved transcriptional control. Thus, the second aim in these studies is to understand the mechanism by which insulin rapidly shuts off glucose output by the liver and how this process becomes defective in the absence of Akt2. Lastly, a paradoxical aspect of insulin resistant syndromes is that, even though the liver is alleged to be insensitive to the actions of insulin, its metabolic phenotype regarding lipids appears to be "hyper-responding" to insulin. The Principal Investigator and his laboratory favor the hypothesis that insulin resistance under pathological conditions is "selective", retaining the ability of insulin to regulate anabolic lipid pathways while losing suppression of hepatic glucose output. The phenotype of livers deficient in Akt2, which are protected from accumulation of fat in the liver, support this hypothesis. The third aim of these studies understands mechanistically the requirement for Akt2 in the accumulation of neutral lipid in the mouse liver during pathological, insulin-resistant states. It is hoped that through these detailed investigations into the metabolic actions of insulin in the liver, it will be possible to arrive at new therapeutic targets to combat the ravages of Type II Diabetes Mellitus. PUBLIC HEALTH RELEVANCE: Recent years have witnessed an increase in obesity and diabetes mellitus of epidemic proportions. One of the central abnormalities in these states is abnormal production of lipids in the liver, which contributes to the heart disease that is so often a major problem in Type II Diabetes Mellitus. It is the aim of these studies to understand why lipid metabolism is so disturbed in Type II Diabetes Mellitus and to identify novel targets to treat this aspect of the disease.